TB Skin Testing, Anergy and Preventive Therapy

Jichard E. Chaisson, M.D.

While it has been clear for some time that HIV-infected, tuberculin skin
test (PPD) -- positive individuals have a high risk of progression to active
tuberculosis, the importance of anergy has been very controversial. Several
early reports noted high rates of active tuberculosis in HIV seropositive people
who were anergic by PPD testing and controls. In a report by Selwyn and
associates from New York (JAMA 1992; 268:504-509), the rate of TB in
HIV-infected drug users who were anergic by PPD and the CMI Multitest (Merieux
Diagnostics) was 6.6 cases per 100 person-years. However, in that study the
rate of TB in HIV seropositive, PPD negative nonanergic persons was not
reported. Nonetheless, as a result of this report, the Centers for Disease
Control and Prevention recommended that HIV-infected patients undergo routine
PPD skin testing and that anergy testing be performed to aid in the
interpretation of negative PPD tests. The CDC also recommended that isoniazid
preventive therapy be considered for HIV seropositive anergic individuals from
populations with a background prevalence of TB infection >10%.

Several important questions about these guidelines were initially unanswered,
but recent studies have led to a thorough reassessment of the use of anergy
tests to help identify candidates for TB prophylaxis.

How reliable is anergy testing and what do the results mean?

While the PPD skin test has been extensively studied and validated, anergy tests
have not undergone similar scrutiny. The antigens used have never been
standardized and the interpretation of anergy testing has not been validated.
Several recent reports suggest that anergy testing has poor predictive value in
HIV-infected people.

Markowitz et al. (Ann Intern Med 1993; 119:185-193) in the Pulmonary
Complications of HIV Study found no association between PPD results and anergy
results. In a study of more than 1000 HIV-infected persons, the investigators
reported that the prevalence of a positive PPD (>5 mm induration) was 6% in
patients with a positive control test (i.e. non-anergics) and 7% in those who
were anergic. Thus, response to the anergy test did not predict response to
PPD.

Caiaffa and associates (Arch Intern Med 1995; 155:2111-2117) performed PPD
skin tests and anergy panels in a cohort of injection drug users in Baltimore.
Among those individuals who were initially non-anergic, 24% of HIV
seropositives and 15% of HIV seronegatives developed anergy when retested 6-12
months later. Among those who were initially anergic, however, 44% of HIV
seropositives and 66% of HIV seronegatives were not anergic when retested. The
authors concluded that anergy tests were unstable over time and of dubious
value in individual patients.

Chin and associates (Am J Respir Crit Care Med 1996; 153:1982-1984) studied
491 HIV-infected individuals in the Pulmonary Complications of HIV Study, as
well. They found that 30% of initially anergic individuals became non-anergic
on follow-up testing. They also reported that "false positive" mumps
anergy tests were found in 39% of subjects who had previous positive tuberculin
skin tests that had become negative. They concluded that anergy testing could
not be relied upon for helping to interpret the results of a negative PPD.

Do anergic individuals who later develop active TB have reactivation of
latent infection or primary TB from a recent exposure?

In the study of Selwyn et al., the five HIV seropositive, anergic
patients who developed active TB during follow-up had clinical features
consistent with primary infection. While it is impossible to distinguish recent
from remote TB infection in the HIV-infected patient without DNA fingerprinting,
these cases occurred during the extraordinary epidemic of TB in New York City
during the late 1980s and early 1990s.

In a study by Moreno and associates in Spain (Ann Intern Med 1993;
119:194-198 ), a similar situation prevailed. The rate of tuberculosis in
anergic, HIV seropositive individuals was 12 per 100 person-years of follow up;
the rate among HIV seropositive, PPD negative, non-anergic persons was 6 per
100 person-years. This latter rate, while significantly lower than that of
anergics, is exceptionally high and represents epidemic tuberculosis.

Thus, it is not clear that the tuberculosis that occurs in anergic individuals
really is a result of reactivation of latent infection. Therefore, the value of
providing routine prophylaxis with isoniazid could not be predicted based on
the earlier studies.

Should anergic, HIV seropositive individuals from high TB-prevalence
populations be given chemo-prophylaxis?

Two recent studies
strongly suggest that the routine prescription of chemoprophylaxis to anergic
patients is not efficacious or effective.

Graham and coworkers (Arch Intern Med 1996; 156:889-894) performed PPD
and anergy skin tests on a cohort of injection drug users in Baltimore. All
participants with a reactive PPD (>5 mm for HIV seropositives and >10 mm
for seronegatives) were given isoniazid prophylaxis under direct supervision
twice weekly for six months. HIV seropositives were also given an additional
six months of self-supervised isoniazid. Anergic HIV seropositives did not
receive prophylaxis. After the introduction of prophylaxis for the PPD positive
drug users, cases of tuberculosis dropped dramatically (over 80% decrease in
risk) in the cohort, falling to zero in the last 18 months of the study.
Despite a background prevalence of tuberculin positivity that was 25%, no
anergic or PPD negative individual developed tuberculosis. This ecologic study
demonstrates the value of providing isoniazid prophylaxis to PPD positive, HIV
seropositive patients, and suggests that prophylaxis is unnecessary for anergic
individuals in a setting where tuberculosis is not epidemic.

Gordin and associates performed a randomized, double-blind,
placebo-controlled trial of isoniazid prophylaxis for HIV seropositive, anergic
individuals from populations with a background prevalence of tuberculous
infection that was at least 10% (ICAAC, Late Breaker Session, 1996). Patients
were treated with isoniazid 300 mg daily or placebo for six months. With an
average of two years of follow up, the rate of tuberculosis in the placebo group
was 0.9 cases per 100 person-years versus 0.4 cases per 100 person-years in the
isoniazid group (p=not significant). This study also demonstrated a low rate of
tuberculosis in anergic, HIV seropositive patients from high prevalence
populations, and found no clinically or epidemiologically significant benefit to
isoniazid preventive therapy in this setting.

The collective results of these recent studies indicate that anergy testing
is much ado about nothing. Given the instability and lack of predictive value
of anergy testing, the use of these imprecise tests in clinical practice cannot
be endorsed. The results of the prospective randomized trial of Gordin and
coworkers is powerful evidence that isoniazid prophylaxis is not efficacious for
anergic, HIV-infected patients in the United States. Whether prophylaxis would
be useful in settings where tuberculosis is more prevalent in the community,
such as in many developing nations, is not now known. The United States Public
Health Service/Infectious Disease Society of America Working Group on Prevention
of Opportunistic Infections in HIV-infected Persons will reconvene in November
1996 to consider changes in the current recommendations for anergy testing and
chemoprophylaxis. It seems likely that the data described in this article will
prompt a change away from anergy testing and a greater concentration on
identifying and providing prophylaxis to PPD positive persons with HIV
infection.